ABSTRACT Alzheimer?s disease (AD) has a long presymptomatic period characterized by the co-existence of several pathophysiological processes leading to overt neuronal damage. Despite the well-established findings of brain atrophy in the later (symptomatic) stages of AD, the trajectory of these structural changes along the AD continuum remains controversial. Importantly, recent studies have demonstrated evidence for changes in the microstructural properties of the brain tissue in the cortical mantle occurring already in the preclinical stage of the disease, and these changes have been suggested to play an important role in the early pathophysiology of AD. However, the impact of these early microstructural changes on disease progression remains understudied, mainly due to the limited methodological approaches to study them in the human brain. The recent advent of a novel methodological neuroimaging approach using diffusion-weighted imaging (DWI) technique, has made it possible to quantifying microstructural changes by means of cortical mean diffusivity in the grey matter. Previous studies using this technique have demonstrated microstructural changes in preclinical AD as well as presymtomatic mutation carriers of autosomal dominant AD, support the notion that microstructural changes are occurring early in the disease process. However, the mechanism by which early regional A? deposits in the brain are related to microstructural changes, and how their interactions may lead to further disease progression remains unknown. In this R21 proposal we will validate and further develop advanced DWI MRI methods for detecting the microstructural changes that accompany AD. By using multimodal, state-of the-art methods the overall objective of this proposal is to visualize the interplay between early microstructural alterations and pathological changes (extracellular A? and tau) across early preclinical stages of AD as well as its relation to cognition. Specifically, using data from an existing NIA-funded, rich multi-modality dataset (Harvard Aging Brain Study) of cognitively normal older individuals the proposed work will determine the cross-sectional regional relationship of microstructural changes with amyloid A? burden, as measured with PiB-PET (Aim 1). Furthermore, we will use longitudinal data to determine whether microstructural changes at baseline portends increased tau deposition, as measured with T807 (Aim 2), and lower cognition (Aim 3) at follow up, and whether A? modifies these relationships. The proposed work may provide critical information to improve our understanding of the mechanistic underpinnings of how microstructural changes are linked to AD pathology, as well as their effect on brain function. As a consequence, the findings could substantially improve our understanding of the evolution of AD etiology and may contribute to the clinical diagnosis of the disease.